Background
Methods
Study inclusion criteria
Types of studies
Types of participants
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overall mean or median age ≥ 65 years,
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overall mean or median age < 65, but subgroup analysis of participants <65, or
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overall mean or median age not reported but more than 80% of studies reported a mean or median age ≥ 65 years.
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≥80% of participants ≥65 years or
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<80% of participants ≥65 years but subgroup analysis of participants <65. We included any setting reporting on the management of hypertension using beta blockers.
Types of interventions
Types of outcomes
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Mortality
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Hospitalization
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Cardiovascular event including stroke
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Quality of life
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Adverse drug event
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Life expectancy
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Cognitive impairment or cognitive status
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Functional impairment or functional status
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Renal failure
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Composite end points including any of the above
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Any of the above evaluated as safety endpoints
Study exclusion criteria
Search method
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Search 1 was conducted on 11 September 2013 and updated on 22 December 2015 in the Cochrane Database of Systematic Reviews (OVID interface, 2005 to December 2015) and the Database of Abstracts or Reviews of Effects (DARE, OVID interface, 1991 to 2nd Quarter 2015).
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Search 2 was conducted on 17 October 2013 and updated on 22 December 2015 in MEDLINE (OVID interface, In-Process & Other Non-Indexed Citations 1946 to November Week 3 2015), EMBASE (OVID interface, 1974 to 2015 December 21), Health Technology Assessment (HTA, OVID interface 2001 to 4th Quarter 2015) and International Pharmaceutical Abstracts (IPA, OVID interface 1970 to December 2015).
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Search 3A consisted of eligible individual studies identified from systematic reviews and meta-analyses excluded from searches 1 and 2 covering the time of these searches.
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Search 3B was conducted on 28 September 2016 in MEDLINE (OVID interface, 2005 to 2016), EMBASE (OVID interface, 2005 to 2016), HTA (OVID interface 2005 to 2016) and IPA (OVID interface 2005 to September 2016). The result of search 3B was limited to the last 5 years (1 January 2011 to 28 September 2016) because search 3A had already used a high quality Cochrane review [17] which had covered all individual studies eligible for the time before 2012 (see 3A). This Cochrane review has recently been updated, and again, no additional eligible studies for our review were identified [22].
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Our hand search comprised a review of the bibliographies of all included studies.
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Study protocols from all searches were also collected to consider for future updates of this systematic review.
Selection of studies and data management
Data extraction
Quality appraisal
Data synthesis
Identification of additional “references of interest” and the development of recommendations
Recommendation | Strength of the recommendation | Quality of the evidence | Type of evidence |
It is suggested to discontinue the beta blocker or change it to another antihypertensive drug (unless another indication for beta blockers exists), because beta blockers may increase the risk of stroke and other composite cardiovascular outcomes compared to other antihypertensive agents while not revealing any benefit regarding cardiovascular outcomes or mortality compared to placebo for adults >60 years. | Strong | Low Downgraded for indirectness because only one meta-analysis and one RCT were focused on older people | |
It is suggested to discontinue atenolol for the management of hypertension because it appears to be less effective than other antihypertensives in reducing cardiovascular events, and to have a higher risk of adverse events. | Strong | Low Downgraded for indirectness because only one RCT was focused on older people | |
It is suggested to discontinue beta blockers as monotherapy for the management of hypertension because it may be inferior to other antihypertensives in preventing stroke, and not to have any benefits in decreasing the rates of cardiovascular events. This recommendation does not apply if the patient has other indications for beta blockers (heart failure, arrhythmia, previous myocardial infarction, angina pectoris). | Strong | Low Downgraded for indirectness because only the meta-analysis included a subgroup analysis in older people |
Results
Results of the search
Characteristics of the included studies
Khan et al. 2006. Re-examining the efficacy of β–blockers for the treatment of hypertension: a meta-analysis, CMAJ, 174(12): 1737-42 [33] | ||
Country | Canada | |
Funding | Not stated | |
Setting | Not stated | |
Objective | To explore the efficacy (stroke, myocardial infarction and death) of beta blockers in different age groups | |
Inclusion and exclusion criteria
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Population | Hypertension, distinguish between “younger” patients <60 years (mean age ranged from 45.5 to 56.2 years, n=10 trials and n=50,612 patients) and “older” patients ≥60 years (60.4 to 76 years, n=11 trials and n=95,199 patients, 9 trials out of 11 with mean age ≥65 years). | |
Intervention | Beta blocker as first-line therapy for hypertension in preventing major cardiovascular events | |
Control | No treatment, placebo, diuretic, ACE inhibitor, calcium-channel blocker, angiotensin-receptor blocker | |
Outcomes | Stroke, myocardial infarction, or death | |
Study designs | Randomized controlled trials | |
Methods
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Study design | Systematic review including meta-analysis. Results of the individual studies are combined to produce an overall statistic. | |
Last date searched | 18 January 2006 | |
Data bases searched | PubMed (1950-18.01.2006) | |
Other sources searched | Hand search, reference lists of published hypertension meta-analysis (MEDLINE) and the Cochrane Library. Contacted Canadian hypertension experts. | |
Number of included studies | 21 Randomized controlled trials | |
Number of included patients | 145,811 | |
Outcomes, results
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Primary
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Composite cardiovascular outcome of death, nonfatal myocardial infarction or nonfatal stroke | Beta blockers reduced event rates compared with placebo (RR 0.86, 95% CI 0.74–0.99, based on 794 events in 19,414 patients), in trials enrolling younger patients, but benefits were not found in trials enrolling older patients (RR 0.89, 95% CI 0.75–1.05, based on 1115 events in 8,019 patients). Among 30,412 patients younger than 60 years of age, there was no difference in event rates between those randomly assigned to beta blockers therapy compared with those receiving other antihypertensive agents (1515 events, RR 0.97, 95% CI 0.88–1.07). However, in the 79,775 patients 60 years of age or older, beta blockers were associated with a higher risk of events than other antihypertensive agents (7405 events, RR 1.06, 95% CI 1.01–1.10). | |
Secondary
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Beta blocker compared to placebo
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“Younger population” < 60 years
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“Older population” ≥ 60 years
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Death | RR 0.94, 95% CI 0.79–1.10 | RR 0.91, 95% CI 0.74–1.12 |
Nonfatal myocardial infarction | RR 0.85, 95% CI 0.71–1.03 | RR 0.98, 95% CI 0.83–1.16 |
Nonfatal stroke | RR 0.84, 95% CI 0.65–1.10 | RR 0.78, 95% CI 0.63–0.98 |
Heart failure | RR 1.05, 95% CI 0.72–1.54 | RR 0.54, 95% CI 0.37–0.81 |
Beta blocker compared to other antihypertensive agents
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“Younger population” < 60 years
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“Older population” ≥ 60 years
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Death | RR 0.97, 95% CI 0.83–1.14 | RR 1.05, 95% CI 0.99–1.11 |
Nonfatal myocardial infarction | RR 0.97, 95% CI 0.86–1.10 | RR 1.06, 95% CI 0.94–1.20 |
Nonfatal stroke | RR 0.99, 95% CI 0.67–1.44 | RR 1.18, 95% CI 1.07–1.30 |
Heart failure | RR 0.93, 95% CI 0.64–1.34 | RR 0.98, 95% CI 0.87–1.11 |
Subgroup analysis, ≥60 years
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Beta blocker compared to placebo or no treatment
(5 trials and n=8,019 patients, range mean age 65 to 75.7 years) | ||
Composite cardiovascular outcome of death, nonfatal myocardial infarction or nonfatal stroke | Beta-blockers´ benefits were not found in trials enrolling older patients RR 0.89, 95% CI 0.75–1.05, based on 1,115 events in 8,019 patients. | |
Death | RR 0.98, 95% CI 0.83–1.16 | |
Nonfatal myocardial infarction | RR 0.98, 95% CI 0.83–1.16 | |
Nonfatal stroke | RR 0.78, 95% CI 0.63–0.98 | |
Heart failure | RR 0.54, 95% CI 0.37–0.81 | |
Beta blocker compared to other antihypertensive agents
(7 trials and n=87,180 patients, range mean age 60.4 to 76 years) | ||
Composite cardiovascular outcome of death, nonfatal myocardial infarction or nonfatal stroke | Beta blockers were associated with a higher risk of events than were other antihypertensive agents (7,405 events, RR 1.06, 95% CI 1.01–1.10). | |
Death | RR 1.05, 95% CI 0.99–1.11 | |
Nonfatal myocardial infarction | RR 1.06, 95% CI 0.94–1.20 | |
Nonfatal stroke | RR 1.18, 95% CI 1.07–1.30 | |
Heart failure | RR 0.98, 95% CI 0.87–1.11 | |
Conclusion
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Beta blockers should not be considered first-line therapy for older hypertensive patients without another indication for these agents; however, in younger patients beta blockers are associated with a significant reduction in cardiovascular morbidity and mortality. | ||
Quality appraisal
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Quality criteria for systematic reviews and meta-analyses
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Author´s judgement
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Support for judgement
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Precise and accurately defined research question (e.g. PICO) | Yes | Criteria for considering studies are explicitly explained in the paper. The PICOS scheme can be applied |
Well-defined selection criteria | Yes | See above |
Was an ‘a priori’ design provided? | No | There is no published protocol for this meta-analysis |
Systematic literature research | Yes | Search method is illustrated |
Appropriate search strings, data bases and hand search | No | Only a PubMed search and a hand search were conducted. A very limited search string was used. |
At least two reviewers for selecting retrieved studies | Unclear | The review process, screening abstracts and reading full texts is not described. Two authors extracted outcome data from each trial independently. The inter observer kappa for trial inclusion was 0.94 |
Well documented process of selection of included studies (e.g. PRISMA flow diagram) | Unclear | Some kind of PRISMA flow was used, but the review process is unclear. A list of excluded studies is missing. |
Quality of the studies documented and considered for the synthesis of evidence | No | Quality appraisal of studies is lacking |
Was the conflict of interest stated? | Yes | None declared. |
Assessed publication bias | No | Publication bias not assessed |
Heterogeneity statistically analysed | Yes | X2 tests were used to test heterogeneity |
Quality of internal validity
| Poor | No study quality assessment was performed |
Author year | Type of study | Aim | Intervention/control | Sample size | Follow-up | Outcomes and measurement tools if applicable |
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Carlsson 2014 [43] | Cohort study | To study mortality rates in men and woman with hypertension and AF prescribes different cardiovascular pharmacotherapies (time to death between registration of AF diagnosis and 31.12.2007) | Antithrombotic drugs alone: - antiplatelet agents vs. no treatment - anticoagulants vs. no treatment - anticoagulants vs. antiplatelets Beta blocker: - Selective vs. no treatment - non-elective vs. no treatment - non-selective vs. selective RAS-blocking agents: - vs. no treatment - ARBs vs. ACE inhibitors - RAS blocking agents + other vs. no treatment - ARB + thiazide vs. ACE inhibitor + thiazide Calcium receptor- blocking agents: - Vessel selective vs. no treatment - Heart active vs. no treatment - Vessel selective vs. heart active - - Statins |
n = 5602 4748 aged ≥65 y 854 aged <65 y | Mean follow-up 3.4 years | Mortality |
Collier 2011 [42] | Multicentre, international randomized trial | To evaluate the efficacy and safety of an amlodipine versus an atenolol-based antihypertensive regimen among older (≥ 65 years) and younger (<65 years) patients. | Atenolol-based (atenolol ± thiazide diuretic) Amlodipine-based (amlodipine ± perindopril) |
n = 19,257 8137 aged ≥65 and 11,020 aged <65 | Median follow up 5.5 years | Nonfatal myocardial infarction and fatal coronary heart disease and cardiovascular events |
Coope 1986 [34] | RCT | To explore, if the treatment of hypertension in patients between the ages of 60 and 79 years old reduces the incidence of stroke or coronary disease or affects cardiovascular or overall mortality | Intervention group: Step 1: atenolol 100 mg If blood pressure control was insufficient the further treatment steps were applied: Step 2: bendrofluazide 5 mg Step 3: alphamethyldopa 500 mg (and eventually nifedipine retard 20 mg or other antihypertensive medication) Control group: usual care |
n = 884, intervention group n = 419 control group n = 465 | Mean follow up 4.4 years (range 1–10, SD not reported) |
Primary outcomes: myocardial infarction, major strokes, minor strokes, transient ischaemic attacks, death
Secondary outcomes: Congestive heart failure Heart failure Atrial fibrillation Clinical gout Diabetes Non- fatal cancer Vertigo Dizzy spells |
Subgroup analysis in Coope 1986 [34] | See above | To analyse whether the treatment of hypertension in patients between the ages of 70 and 79 years old reduces the incidence of all strokes | See above | Not stated | Not stated | Incidence of all strokes including major strokes, minor strokes, transient ischaemic attacks |
Gelber 2013 [45] | Prospective, community- based cohort study | To determine the associations between classes of antihypertensive medication use and the risk of cognitive impairment among elderly hypertensive men. | No drug, BB alone, ACE alone, Diuretic alone, CCB alone, vasodilators alone, BB & 1 other, Other drug combinations |
n = 2197 | Median follow up 5.8 years (SD 5.1) | Development of cognitive impairment CASI Score, a combination of the Hasegawa Dementia Screening Scale, the Folstein Mini-Mental State Examination, and the Modified Mini-Mental State Examination |
Pepine 2003 [32] | RCT | To test the hypothesis, that the risk for adverse outcomes in older people with hypertension and coronary artery disease treated with a calcium antagonist based strategy or a non-calcium antagonist (atenolol) based strategy is equivalent. |
Step 1: either calcium antagonist group: 240 mg/d of verapamil sustained release or non-calcium antagonist: 50 mg/d of atenolol If target blood pressure was not achieved, further steps:
Step 2:
calcium antagonist group additional trandolapril non-calcium antagonist group additional hydrochlorothiazide
Step 3: dosage increase
Step 4:
calcium antagonist group additional hydrochlorothiazide non-calcium antagonist group additional trandolapril. |
n = 22,576 Calcium antagonist group, n = 11,267 Non-calcium antagonist group, n = 11,309 | Mean follow up 2.7 years (range 1 day to 5.4 years, SD not reported) |
Primary outcome:
first occurrence of -death (all cause) -non-fatal myocardial infarction -non-fatal stroke
Secondary outcomes:
death (all cause), non-fatal myocardial infarction, non-fatal stroke, time to most serious event (ranked from death as most serious, to myocardial infarction, to stroke as last serious), cardiovascular death, angina, cardiovascular hospitalizations, cancer, Alzheimer disease, Parkinson, gastrointestinal bleeding, blood pressure control, new diagnosis of diabetes, adverse experiences. |
Subgroup analysis in Pepine 2003 [32] | See above | See above | See above | Subgroup >70 years old: calcium antagonist group: n = 3694 non- calcium antagonist group: n = 3829 | See above | See above |
Ruwald 2012 [41] | Post hoc analysis of a double-blind, double-dummy randomized trial | To investigate the influence of age on the effects of losartan versus atenolol-based antihypertensive treatment | Intervention: losartan 50 mg (step 2: + HCT 12.5 mg HCT step 3: losartan 100 mg + HCT 12.5 mg step 4: losartan 100 mg + HCT 12.5-25 mg HCT + another antihypertensive treatment) Control: atenolol 50 mg (step 2: + HCT 12.5 mg step 3: atenolol 100 mg + HCT 12.5 mg step 4: atenolol 100 mg + HCT 12.5-25 mg + another antihypertensive treatment) |
n = 9193
n = 4304 < 67 years (46.8%)
n = 4889 ≥ 67 years (53.2%) | Mean follow up 4.8 years |
Primary outcome:
Composite of cardiovascular death, nonfatal stroke, nonfatal MI |
Testa 2014 [44] | Cross sectional study | To evaluate long-term mortality in hypertensive older adults taking atenolol | No atenolol (Intervention)/atenolol (control) | 972 patients aged ≥65 with isolated hypertension mean age 74.4 ± 6.4 | Follow up of 12 years from 1992 to 2003 (not stated if median or mean follow up) | Taking atenolol showed a greater mortality (73.9% vs 55.0%; p = 0.047) and higher pulse arterial pressure values (74.7 vs 63.02 mmHg, p < 0.001) than those not taking atenolol. Atenolol use (HR 1.91; 95% CI: 1.04–4.31; p = 0.04) was predictive of long-term mortality. Pulse arterial pressure (HR 1.02; 95% CI 1.01–1.03; p = 0.032) was weakly predictive of long-term mortality. |
Studies based on the COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events) trial
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Matsuzaki 2011 [35] Main trial | multicentre, prospective, randomized, open-label, blinded-endpoint trial | To determine the optimal CCB benidipine-based combination therapy (angiotensin-receptor blocker (ARB), beta-blocker or a thiazide) in terms of lowering BP and preventing cardiovascular events | 3 intervention arms: 1. ARB (benidipine 4 mg + angiotensin receptor blocker usual dose) 2. BB (benidipine 4 mg + beta-blocker usual dose) 3. TD (benidipine 4 mg + half daily dose of thiazid diuretic step 2: benidipine 8 mg (plus ARB/BB/TD) step 3:benidipine 8 mg plus dose increase of ARB/BB/TD |
n = 3293 1. ARB n = 1110 (analysed) 2. BB n = 1089 (analysed) 3. TD n = 1094 (analysed)
n = 1533 ≥ 65 years (46.6%)
n = 1760 < 65 years (53.4%) | Median follow up 3.61 years |
Primary outcome: composite of cardiovascular morbidity and mortality (sudden death, fatal or non-fatal stroke, fatal or non-fatal myocardial infarction, hospitalization due to unstable angina, new onset of heart failure new onset or worsening of peripheral arterial disease, new onset or worsening of renal failure)
Secondary outcomes:
(1) All-cause mortality (2) Death from cardiovascular events (3) Fatal and non-fatal cardiovascular events (4) New onset of diabetes mellitus (5) Safety (adverse events and adverse drug reaction) (6) Nonfatal stroke Hospitalization due to heart failure (results on outcome not reported) |
Ogihara 2012 [40] COPE trial | post hoc analysis of the COPE trial | To evaluate the efficacy and safety in older (≥65 years) and younger (<65 years) hypertensive patients | ||||
Studies based on the Medical Research Council (MRC) trial
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MRC 1992 [33] Main trial | RCT | To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke, coronary heart disease, and death. | Patients were randomized to atenolol 50 mg daily; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg (Moduretic©) daily; or placebo. |
n = 4396 Three groups (a) potassium sparing diuretic regimen (hydrochlorothiazide +amiloride) n = 1081 (b) beta blocker atenolol n = 1102 (c, d) matching placebo tablets
n = 2213 | Mean follow up 5.8 years 25,355 patients years of observation (SD not reported) | Strokes, coronary events, and deaths from all causes. |
Bird 1990 [36] | RCT, secondary analysis | To explore if cognitive dysfunction, manifested as an increased incidence of confusional states or impaired concentration and attention are associated either with a particular antihypertensive regime or with the reduction in blood pressure level that it induces. To explore if a continuous reduction in mildly elevated blood pressure levels affect the rate of change in cognitive function. | Patients were randomly assigned to hydrochlorothiazide 25 mg and 2.5 mg amiloride, (Moduretic©) daily, atenolol 50 mg daily, or placebo. |
n = 2401 hydrochlorothiazide amiloride 24% atenolol 24% Placebo 52% | Results reported at month 1 and 9 (median or mean follow up and SD not reported) | Cognitive tests: Verbal intelligence measured with the Nelson Adult Reading Test (NART), Non verbal intelligence (performance ability) measured with the Ravens Matrice, part a & b, Capacity to learn and remember new material measured with the Paired Associate Learning Test (PALT), Alertness and speed of reaction measured with the Trail-Making Test (TMT), Depression with the self-rating Depression Questionnaire (DQ) Blood Pressure |
Carr 2012 [37] | RCT, secondary analysis | To assess the impact of the blood pressure profile on cardiovascular risk in the Medical Research Council (UK) elderly trial and to investigate whether the effects of hypertensive drugs in reducing event rates are solely a product of systolic pressure reduction. | Intervention:1. atenolol 50 mg daily or 2. hydrochlorothiazide 25 mg (50 mg) + amiloride 2,5 mg (5 mg) Control: Placebo |
n = 4396 atenolol: n = 1102 hydrochlorothiazide + amiloride: n = 1081 hydrochlorothiazide + Placebo n = 2213 | Mean follow up 5.8 years |
Primary outcomes:
stroke CHD
secondary outcomes:
association between BP and outcomes |
Lever 1992 [48] | RCT, secondary analysis | To study the effect of two treatments for hypertension on all-cause mortality and morbidity from cardiovascular disease | see above | see above | see above | Stroke coronary events all cardiovascular events all-cause mortality withdrawal/loss to FU from treatment |
Lever 1993 [38] | RCT, secondary analysis | To determine whether hypotensive drug treatment in men and women aged 65–74 reduces stroke, CHD and mortality | see above | see above | see above | Stroke coronary events all cardiovascular events all-cause mortality change in blood pressure |
Participants
Author year | Setting / country / ethnicity | Male sex | Agea
| Reported comorbidities | Reported concomitant medications | Functional status/Frailty level | Cognitive status |
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Carlsson 2014 [43] | Sweden | 50.14% | Men: mean age 72.3 years, 79% ≥ 65 years. Woman: mean age 77.2 years, 92% ≥ 65 years | Diagnosis of both AF and hypertension (inclusion criteria), coronary heart disease, cerebrovascular diseases, including intracranial bleeding and peripheral embolism, congestive heart failure, DM II | - Diuretic drugs (thiazides, related agents, combined formulations with other drugs, loop diuretics, potassium-saving diuretics) - Beta blocker (ß1-selective, non-selective) - Calcium receptor-blocking agents (vessel-selective, heart-selective) - RAS-Blockers (ACE-inhibitors, ARBs) - Lipid-lowering drugs (statins) - antithrombotic drugs | Not reported | Not reported |
Collier 2011 [44] | UK, Sweden, Denmark, Iceland, Norway, and Finland | Patients ≥65 Amlodipine-based regimen 73.6% Atenolol-based regimen 73.5% | Patients ≥65 Amlodipine-based regimen 71.1 (4.0) Atenolol-based regimen 71.1 (4.0) | Type 2 diabetes mellitus, ECG abnormalities (not LVH), LVH (on ECG or ECHO), Peripheral vascular disease | No previous antihypertensive use, n (%): Amlodipine-based regimen 681 (16.8) Atenolol-based regimen 677 (16.5) Aspirin use, n (%): Amlodipine-based regimen 1066 (26.4) Atenolol-based regimen 1046 (25.5) | Not reported | Not reported |
Coope 1986 [37] | 13 general practices in England and Wales | Intervention group: 29.0% Control group: 32.0% | Intervention group: 68.7 (5.2) years Control group: 68.8 (5.1) years | Intervention group Left ventricular hypertrophy on ECG: n = 8 Cardiac enlargement on chest XRay: n = 22 Control group Left ventricular hypertrophy on ECG: n = 11 Cardiac enlargement on chest XRay: n = 21 | Not stated | Not stated | Not stated |
Subgroup analysis in Coope 1986 [37] | See above | 29.1% (based on own calculations) | 70–79 years | Not stated | See above | See above | See above |
Gelber 2013 [45] | Hawaii, USA (Japanese men) | 100% | Overall mean age: 77 No drug 77.2 (4.2) BB alone 76.2 (3.8) ACE alone 76.7 (4.1) Diuretic alone 77.4 (4.0) CCB alone 76.9 (4.0) Vasodilators alone 76.8 (3.6) BB & 1 other 76.5 (3.6) Other drug combi-nation 77.0 (4.0) | Type 2 diabetes mellitus, CVD (defined as history of myocardial infarction, angina and other coronary heart disease or stroke), APOE | Not reported | Not reported | BB use was not significantly associated with a lower risk of cognitive impairment, suggesting that medication class may be less relevant if the SBP is not adequately controlled. |
Pepine 2003 [34] | 862 primary care sites in 14 countries worldwide Calcium antagonist group (%): White 48.5 Hispanic 35.7 Black 13.4 Asian 0.6 Other/multiracial 1.9 Non-calcium antagonist group (%): White 48.3 Hispanic 35.6 Black 35.6 Asian 0.8 Other/multiracial 1.9 | Calcium antagonist group (%): 48.1 Non-calcium antagonist group (%): 47.7 | Calcium antagonist group: 66,0 (9.7) years Non-calcium antagonist group: 66,1 (9.8) years | Calcium antagonist group (%): Myocardial infarction 32.1 Prior myocardial infarction or abnormal angiogram 52.6 Angina pectoris 66.2 CABG ≥1 month ago 15.5 PCI ≥ 1 month ago 15.2 CABG or PCI 27.3 Stroke 5.3 Left ventricular hypertrophy 21.5 Unstable angina ≥1 month ago 11.4 Arrhythmia 7.1 Heart failure class II-III 5.5 Peripheral vascular disease 11.9 Diabetes 28.1 Hypercholesterolemia 55.9 Renal impairment 1.9 Cancer 3.5 Non-calcium antagonist group (%): Myocardial infarction 31.8 Prior myocardial infarction or abnormal angiogram 53.3 Angina pectoris 67 CABG ≥1 month ago 16.1 PCI ≥ 1 month ago 14.7 CABG or PCI 27.3 Stroke 5.0 Left ventricular hypertrophy 22.3 Unstable angina ≥1 month ago 11.5 Arrhythmia 7.1 | Calcium antagonist group (%): Aspirin© or other antiplatelet inhibitors 57 NSAIDsb 17.6 Antidiabetic medication 22.1 Any lipid-lowering agent 36.8 Nitrates 35.4 Potassium supplement 6.9 Hormone replacement 17.7 Non-calcium antagonist group: Aspirin© or other antiplatelet inhibitors: 56.4 NSAIDs: 17.9 Antidiabetic medication: 22.9 Any lipid-lowering agent: 36.6 Nitrates: 36.6 Potassium supplement 6.9 Hormone replacement 18.5 | Not stated | Not stated |
Heart failure class II-III 5.6 Peripheral vascular disease 12.0 Diabetes 28.6 Hypercholesterolemia 55.6 Renal impairment 1.9 Cancer 3.3 | |||||||
Subgroup analysis in Pepine 2003 [34] | Not stated | Not stated | >70 years | Not stated | Not stated | Not stated | Not stated |
Ruwald 2012 [40] | Denmark, Finland, Iceland, Norway, Sweden, and UK, | 45–66 years: losartan: 51.2% atenolol: 50.6% 67–83 years: losartan: 41.3% atenolol: 42.0% | overall mean age 67 years 46.8% <66 years 53.2% ≥67 years | Any vascular disease: 25% (Coronary heart disease 16%, cerebrovascular disease 8%, peripheral vascular disease 6%), atrial fibrillation: 4% diabetes: 13% isolated systolic hypertension: 14% | Not reported | Not reported | Not reported |
Testa 2014 [46] | Campania/Southern Italy | 41% | Mean age 74.4 (±6.4) 93% ≥ 65 y. | Hypertension (inclusion criteria) Diabetes, chronic renal failure, AF | ACE-inhibitors, diuretics, hypolipidemic drugs | BADL (basic activities of daily living) GDS (geriatric depression scale) | MMSE: Atenolol vs. no Atenolol 24.9 vs. 25.1 (p = 0.841) |
Studies based on the COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events) trial
| |||||||
Author year
|
Setting / country / ethnicity
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Male sex
|
Age
|
Reported comorbidities
|
Reported concomitant medications
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Functional status/Frailty level
|
Cognitive status
|
COPE trial Matsuzaki [47] Main trial | Japan | Overall: benidipine plus -ARB: 51% -BB: 50.5% -TD: 50.5% | Benidipine plus -ARB: 63.0 (10.6) -BB: 63.2 (10.8) -TD: 63.1 (10.8) | ARB/BB/TD groups: Overall: previous casdiovascular disease: 13%/11.4%/12.5% Arrhythmia: 2.7%/3.0%/2.4% Diabetes: 13.9%/14.2%/14.4% | ARB/BB/TD groups: Overall: Antiplatelet agents: 8.9%/6.8%/7.3% Lipid-lowering agents: 21.1%/20.4%/21.2% Antidiabetic agents: 6.9%/7.3%/7.2% | Not reported | Not reported |
Ogihara [41] | ≥65 years: -ARB: 43.6% -BB: 43.8% -TD: 42.3% | 46.6% aged ≥65 years (≥65 years: mean age 72.6 years) | ≥65 years: previous cardiovascular disease: 18.3% stroke: 4.4% angina pectoris: 4.8% MI: 1.05/0.7%/1.2% Arrhythmia: 3.6%/3.9%/3.6% Diabetes: 16.5%/16.5%/16.8% | ≥65 years: Antiplatelet agents: 13.7%/10.7%/11.8% Lipid-lowering agents: 23.1%/21.7%/20.4% Antidiabetic agents: 8.6%/9.2%/9.0% | |||
Studies based on the Medical Research Council (MRC) trial
| |||||||
Author year
|
Setting / country / ethnicity
|
Male sex
|
Age
|
Reported comorbidities
|
Reported concomitant medications
|
Functional status/Frailty level
|
Cognitive status
|
MRC 1992 [35] Main trial | 226 general practices in England, Scotland, and Wales | Diuretic 42.0% Beta blocker 41,0% Placebo 42,0% | Range 65–74 years. | Not stated | Not stated | Not stated | Not stated |
Bird 1990 [36] | see above | 41.0% | Mean (SD) 70.3 (2.7) years | see above | see above | see above | see above |
Carr 2012 [42] | see above | 42% | Mean age 70.3 years Placebo 70.3 Diuretic 70.3 b-blocker 70.4 | see above | see above | see above | see above |
Lever 1992 [48] | see above | see above | see above | see above | see above | see above | see above |
Lever 1993 [39] | see above | see above | see above | see above | see above | see above | see above |
Interventions and outcomes
Any beta blocker
Atenolol
Main findings
Author year | Objective |
---|---|
Kahn 2006 [33] | To explore the efficacy (stroke, myocardial infarction and death) of beta blockers in “younger”(< 60 years) and “older” (≥ 60 years) patients. |
Results:
| |
1. Beta blockers compared to placebo or no treatment
1
(5 trials and n = 8019 patients, range mean age 65 to 75.7 years) | |
Primary outcome: composite cardiovascular outcome of death, nonfatal myocardial infarction or nonfatal stroke | Beta blockers´ benefits were not found in trials enrolling older patients RR 0.89, 95% CI 0.75–1.05, based on 1115 events in 8019 patients. |
Death | RR 0.91, 95% CI 0.74–1.12 |
Nonfatal myocardial infarction | RR 0.98, 95% CI 0.83–1.16 |
Nonfatal stroke | RR 0.78, 95% CI 0.63–0.98 |
Heart failure | RR 0.54, 95% CI 0.37–0.81 |
2. Beta blocker compared to other antihypertensive agents
1
(7 trials and n = 87,180 patients, range mean age 60.4 to 76 years) | |
Primary outcome: composite cardiovascular outcome of death, nonfatal myocardial infarction or nonfatal stroke | Beta blockers were associated with a higher risk of events than were other antihypertensive agents (7405 events, RR 1.06, 95% CI 1.01–1.10). |
Death | RR 1.05, 95% CI 0.99–1.11 |
Nonfatal myocardial infarction | RR 1.06, 95% CI 0.94–1.20 |
Nonfatal stroke | RR 1.18, 95% CI 1.07–1.30 |
Heart failure | RR 0.98, 95% CI 0.87–1.11 |
Authors year | Findings | |||
---|---|---|---|---|
Carlsson 2014 [43] | Prescription of selective or non-selective beta blockers did not affect mortality other than no treatment. Prescription of non-selective beta blockers was associated with lower mortality in sex-adjusted models Full regression model of the whole study sample adjusted for sex and all other covariates: non-selective beta blockers vs. beta 1-selective beta blockers HR 0.62 (95% CI: 0.41–0.95). | |||
men aged ≥80 y
(HR (95
%CI)): beta 1-selective vs. no treatment: Model A: 1.01 (0.60–1.70) Model B: 1.09 (0.64–1.85) non-selective vs. no treatment: Model A: 0.47 (0.14–1.64) Model B: 0.53 (0.15–1.88) non-selective vs. beta 1-selective Model A: 0.42 (0.13–1.37) Model B: 0.39 (0.12–1.25) |
men all ages (HR (95%CI)):
beta 1-selective vs. no treatment:
Model A: 0.99 (0.69–1.40) Model B: 1.12 (0.77–1.59) non-selective vs. no treatment: Model A: 0.55 (0.28–1.08) Model B: 0.68 (0.34–1.36) non-selective vs. beta 1-selective Model A. 0.57 (0.32–1.05) Model B: 0.54 (0.29–1.01) | |||
women aged ≥80 y(HR (95%CI)):
beta 1-selective vs. no treatment: Model A: 0.87 (0.58–1.31) Model B: 0.90 (0.59–1.38) non-selective vs. no treatment: Model A: 0.77 (0.36–1.64) Model B: 0.76 (0.35–1.64) non-selective vs. beta 1-selective Model A:0.88 (0.44–1.76) Model B: 0.86 (0.41–1.75) |
women all ages(HR (95%CI)):
beta 1-selective vs. no treatment Model A: 0.85 (0.60–1.20) Model B: 0.88 (0.62–1.25) non-selective vs. no treatment Model A: 0.62 (0.33–1.17) Model B. 0.66 (0.34–1.25) non-selective vs. beta 1-selective Model A: 0.76 (0.43–1.35) Model B: 0.73 (0.41–1.31) | |||
Model A (prospensity score age group, cardiovascular comorbidity (diabetes, CHD, CHF and CVDs), educational level and marital status) Model B (propensity score including all variables in Model A and all the antihypertensive drugs, antithrombotics and statins (except the studied drug class). | ||||
Collier 2011 [44] | Compared with the atenolol-based regimen, the amlodipine-based regimen reduced: - the relative risk of cardiovascular events more effectively in both age groups: by 17% in patients ≥65 years (hazard ratio: 0.83; 95% CI 0.75, 0.91; P < 0.01) and 15% in patients <65 years (hazard ratio 0.85; 95% CI 0.78, 0.95; P < 0.01) - cardiovascular mortality by 23% in the older group (hazard ratio 0.77; 95% CI 0.63, 0.94; P < 0.01) and by 24% in the younger group (hazard ratio 0.76; 95% CI 0.58, 1.00; P = 0.05) - fatal and nonfatal stroke by 30% in the older group (hazard ratio 0.70; 95% CI 0.59, 0.84; P < 0.01) and by nonsignificant 9% in the younger group (hazard ratio 0.91; 95% CI 0.71, 1.15; P = 0.42) - - significant in total of coronary endpoints, nonfatal MI (excluding silent MI) and fatal CHD in the younger, but not in the older group | |||
Coope 1986 [37] | Overall no significant difference in the total mortality was found neither in treatment nor in the control group. The rate of all deaths in the intervention group was 0.97 of that in the control group (95% CI 0.70–1.42).The rate of fatal stroke in the intervention group was 0.30 of that in the control group (95% CI 0.11–0.84) p < 0.025. Rate of all stroke in the intervention group was 0.58 of that in the control group (95% CI 0.35–0.96) p < 0.03. The subgroup analysis of patients by age (70–79 years) showed a similar reduction in total stroke in both groups, but the study was not large enough for these differences to be significant. | |||
Gelber 2013 [45] | Beta blocker use as the sole antihypertensive medication was associated with a lower risk of developing cognitive impairment (defined as a CASI [Cognitive Abilities Screening Instrument]) score < 74) compared with untreated men (IRR 0,69; 95% CI 0,50–0,94). Non- beta blocker drug combinations were also associated with a reduced risk (IRR 0,78; 95% CI 0,62–0,98). Cognitive decline (defined as a ≥ 9 point decrease in CASI score) occurred in 1167 men (53.1%). Beta blocker use was also associated with a trend toward a decreased risk of cognitive decline: model 2 IRR 0.78 (95% CI 0.61–1.00) for beta blocker use alone; 0.81 (95% CI 0.64–1.03) for beta blocker in combination with other drugs. None of the other drug categories was significantly associated with cognitive decline. | |||
Pepine 2003 [34] | No significant differences in primary outcome (first occurrence of all-cause death, nonfatal MI or nonfatal stroke) were seen between the calcium antagonist group and the non-calcium antagonist group (RR 0.98 CI 0.90–1.06). No significant differences were seen in these outcomes analysed individually. In the subgroup analysis of patients >70 years the primary outcome occurred in 596 of the 3694 patients of the calcium antagonist group (16.3%) and in 664 of the 3829 patients of the non- calcium antagonist group (17.34%). RR 0.93 (95% CI 0.84–1.03) [p-values missing] | |||
Ruwald 2012 [40] | In this post-hoc analysis of the LIFE study, patients were divided in subgroups of aged 66 or younger and aged 67 or older. In the older subgroup, losartan significantly reduced the risk of the composite primary endpoint of cardiovascular death, nonfatal stroke or nonfatal MI compared to atenolol (HR 0.79, 95% CI 0.69–0.91). In the younger subgroup the effect was not significant (HR 1.03, 95% CI 0.82–1.28). Further subdividing suggested a “cut-off age” of 71 years, above which losartan based treatment is better than atenolol based treatment. | |||
Testa 2014 [46] | Older adults taking atenolol showed a greater mortality and higher pulse arterial pressure values than those not taking atenolol (73.9% vs 55.0%; p = 0.047 and 74.7 ± 14.1 vs 63.0 ± 14.2 mmHg, P < 0.001, respectively). Cox regression analysis showed that atenolol use (HR 1.91; 95% CI 1.04–4.31; p = 0.04) and pulse arterial pressure (HR 1.02; 95% CI 1.01–1.03; p = 0.032) were predictive of long-term mortality. | |||
Matsuzaki 2011 Main trial [47] | For the subgroup ≥70 years: There are no statistical significant differences for the primary cardiovascular endpoint in people over 70 years regarding the three intervention arms. | |||
Primary cardiovascular composite endpoint:
| ||||
Hazard ratio (95%CI)
|
P-value
| |||
beta blocker/ARB: <70 years: 1.24 (0.72–2.12) ≥70 years: 1.21 (0.63–2.33) Overall population: 1.22 (0.80–1.85) | beta blocker/ARB: subgroup: 0.9671 overall: 0.3372 | |||
ARB/TD: <70 years: 1.59 (0.83–3.02) ≥70 years: 0.97 (0.50–1.91) Overall population: 1.26 (0.80–2.01) | ARB/TD: subgroup: 0.3017 overall: 0.3505 | |||
beta blocker/TD: <70 years: 1.96 (1.05–3.66) ≥70 years:1.18 (0.61–2.27) Overall population: 1.54 (0.98–2.41) | beta blocker/TD: subgroup: 0.2698 overall: 0.0567 | |||
The number of patients who discontinued the trial because of serious adverse events was 12 (1.1%), 11 (1.0%), and 11 (1.0%) in the benidipine-ARB, benidipine-beta blocker, and benidipine-thiazide groups, respectively. The percentage of adverse events was similar among the treatment groups: 505 (45.5%), 495 (45.5%), and 522 (47.7%) patients reported adverse events. The following adverse events occurred more frequently in another group or in two groups: bradycardia (benidipine-beta blocker,P < 0.0001), hyperkalemia (benidipine-ARB, P = 0.0395), vertigo (benidipine-b-blocker and benidipine-thiazide, P = 0.0188). | ||||
Ogihara 2012 [41] | In this analysis of the COPE trial with 3293 patients in the subgroup of patients aged 65 years or older, benididpe + beta blocker reduced less fatal and non-fatal strokes than benidipine + TD (HR 2.74 (1.08–6-96) and benidipine +beta blocker was associated with more new onset diabetes than benidipine +ARB (HR 2.47 (1.03–5.91). There was no significant difference regarding the composite primary endpoint, cardiovascular endpoints, and all-cause mortality (benidipine plus beta blocker vs. benidipine plus angiotensine receptor blocker HR 0.99 (0.54–1.82); benidipine plus beta blocker vs. benidipine plus thiazide diuretic HR 1.34 (0.69–2.60). | |||
MRC 1992 [35] Main trial | Overall, the beta blocker group had significantly more withdrawals than the diuretic group for both suspected major side effects (beta blocker 30.2% (n = 333); diuretic 14.8% (n = 160); placebo 3.7% (n = 82), and inadequate blood pressure control (beta blocker n = 12; diuretic n = 1; placebo n = 175). After adjusting for baseline characteristics the diuretic group had significantly reduced risk of stroke (31% 95 CI 3% to 51%, p = 0.04), coronary events (44% 95 CI 21% to 60%, p = 0.0009), and all cardiovascular events (35% 95 CI 17% to 49%, p = 0.0005) compared with the placebo groups. The beta blocker group showed no significant reductions in these end points. | |||
Outcome, no. events
|
Diuretic (n = 1081, 6290 patient years) |
Placebo (n = 2213, 12,735 patient years) |
Relative risk per event/treatment (95% CI,
p
-value) Based on own calculations: | |
Stroke fatal | 16 | 42 | 0.78 (0.44–1.38, p = 0.39) | |
Stroke-nonfatal | 29 | 92 | 0.65 (0.43–0.97, p = 0.04) | |
Stroke total | 45 | 134 | 0.69 (0.49–0.96, p = 0.03) | |
Coronary events fatal | 33 | 110 | 0.61 (0.42–0.90, p = 0.01) | |
Coronary events-non-fatal | 15 | 49 | 0.63 (0.35–1.11, p = 0.11) | |
All cardiovascular events | 107 | 309 | 0.71 (0.58–0.87, p = 0.0012) | |
All cardiovascular deaths | 66 | 180 | 0.75 (0.57–0.99, p = 0.04) | |
All deaths | 134 | 315 | 0.87 (0.72–1.05, p = 0.15) | |
Beta blocker (
n = 1102, 6330 patient years) |
Placebo (n = 2213, 12,735 patient years) | |||
Stroke fatal | 21 | 42 | 1.00 (0.60–1.69, p = 0.99) | |
Stroke-nonfatal | 35 | 92 | 0.76 (0.52–1.11, p = 0.16) | |
Stroke total | 56 | 134 | 0.84 (0.62–1.14, p = 0.26) | |
Coronary events fatal | 52 | 110 | 0.95 (0.69–1.31, p = 0.75) | |
Coronary events-non-fatal | 28 | 49 | 1.15 (0.73–1.82, p = 0.56) | |
All cardiovascular events | 151 | 309 | 0.98 (0.82–1.18, p = 0.84) | |
All cardiovascular deaths | 95 | 180 | 1.06 (0.84–1.34, p = 0.63) | |
All deaths | 167 | 315 | 1.06 (0.90–1.27, p = 0.48) | |
Bird 1990 [36] Study based on the MRC trial population |
Blood pressure (mean mmHg) |
Diuretic group
|
Beta blocker group
|
Placebo groups
|
1 month | 152/80 (n = 635) | 159/79 (n = 624) | 166/85 (n = 1303) | |
9 months | 149/79 (n = 582) | 156/79 (n = 481) | 167/86 (1156) | |
Depression Questionnaire (% of participants with depressed mood) | ||||
1 month | 9.1 (n = 551) | 11.0 (n = 554) | 8.8 (n = 1147) | |
9 months | 10.4 (n = 550) | 10.4 (n = 453) | 9.2 (n = 1092) | |
Paired Associate Learning Test (% of participants with a score ≤ 15) | ||||
1 month | 21.0 (n = 593) | 20.0 (n = 579) | 20.0 (n = 1212) | |
9 months | 21.2 (n = 556) | 19.9 (n = 485) | 18.5 (n = 1116) | |
The Trial-Making Test (seconds) | ||||
1 month, mean (SD) | 54.3 (23.9) (n = 593) | 54.7 (23.9) n = 580) | 55.5 (27.7) (n = 1221) | |
9 months, mean (SD) | 52.4 (33.5) (n = 560) | 53.1 (28.2) n = 460) | 52.2 (25.6) (n = 1122) | |
Antihypertensive treatment with either 25 mg hydrochlorothiazide and 2.5 mg amiloride or atenolol 50 mg for 9 months in a population aged between 65 and 74 years old with moderate raised blood pressure did not impair cognitive function, depression, or behavioural changes which would cause concern in confidants. The study did not find a linear relationship between blood pressure levels in their moderately elevated range and psychometric test scores, nor showed that lowering of blood pressure levels is associated with any impairment of performance on these tests | ||||
Carr 2012 [42] | This secondary analysis of the MRC trial found evidence that atenolol does not perform as well as the hydrochlorothiazide plus amiloride (Moduretic ©) in terms of stroke prevention: Moduretic 41.6 number of events /1000 patient years, beta blocker 50.8% and placebo 60.5% (statistical tests missing). For stroke, we found that after adjusting for current systolic blood pressure variability in systolic blood pressure over time, as measured by the standard residual or root successive variance, contained significant prognostic capability: the rate ratio associated with an increase of 1 standard deviation in the standard residual was 1.25 95% CI 0.86–1.81 and 1.16 95% CI 0.85–1.59 for the root successive variance. | |||
Lever 1992 [48] | In this article reporting on the MRC trial, the beta blocker group showed no significant differences to placebo regarding the outcomes stroke, coronary events, all cardiovascular events and all-cause mortality. | |||
Lever 1993 [39] | In this article reporting on the MRC trial, a RCT with 4396 patients (mean age 70.3 years) randomized to beta blocker, diuretic or placebo, the beta blocker group showed no significant differences to placebo regarding the outcomes stroke, coronary events, all cardiovascular events and all-cause mortality. |
Composite outcome of death, nonfatal stroke and nonfatal myocardial infarction
Mortality
Cardiovascular events – including stroke
Cognitive impairment/status
Adverse events
Risk of bias - meta-analysis
Risk of bias - Clinical trials
Risk of bias - Observational studies
Author year | 1. Focused issue | 2. Appropriate method | 3. Recruitment | 4. Selection of controls | 5. Exposure measured | 6. Outcome measured | 7. Identified confounding factors? | 8. Confounding factors in design/analysis | 9. Follow up complete | 10. Follow up long | 11. Believe results | 12. Results be applied | 13. Results fit evidence |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Carlsson 2014 [43] | u | y | y | y | y | y | u | y | y | y | y | y | y |
Collier 2011 [44] | y | y | y | y | y | y | u | y | u | n | n | y | u |
Gelber 2013 [45] | y | n | u | u | y | y | u | y | n | y | n | n | na |
Testa 2014 [46] | y | y | y | y | y | y | u | y | y | y | u | y | u |